INDUCTION OF IMMUNE TOLERANCE TO DNA: THERAPY FOR SLE

这项建议涉及到开发一种免疫学特异性的 系统性红斑狼疮的治疗。因为这种自体免疫 疾病可能源于自我耐受性的失败，我们建议诱导 对自身抗原的耐受性是一种治疗方法。鉴于……的重要性 系统性红斑狼疮中含有核酸抗原抗体的免疫复合体 诱导对这些抗原的耐受性可能提供一种特异的治疗方法 治疗这种疾病。这一观点得到了证据的支持，即对 自身抗原可由耐受原(即自身抗原共价)诱导 链接到同源免疫球蛋白)。此外，我们已经能够将碎片联系起来 足够长的DNA来适应抗DNA抗体的结合大小 由患有系统性红斑狼疮的小鼠或人类制成的同源免疫球蛋白。初步 研究结果表明，这些耐受原a)影响小鼠狼疮，b) 降低系统性红斑狼疮患者外周血淋巴细胞中抗DNA抗体 患者在体外。此次续签旨在确认和延长这些 初步观察。我们将确定小鼠狼疮是否存在于 BFW1和MRL+/+品系小鼠均可预防或治疗。我们会 还可以确定哪些DNA片段与人丙种球蛋白结合 抑制自发或抗原诱导的最佳耐受剂 体外抗核酸抗原抗体。我们的目标是开发 系统性红斑狼疮患者诱导对DNA无应答的数据库。在……里面 此外，与KLH或破伤风类毒素相关的DNA摘要将用于 用不同来源的正常淋巴样细胞建立抗原特异性模型 来源或SLE患者的PBL来研究细胞的某些方面 人体免疫和耐受机制的体外研究。

This proposal concerns the development of an immunologically specific therapy of Systemic Lupus Erythematosus (SLE). Since this autoimmune disease may stem from a failure of self tolerance, we propose induction of tolerance to autoantigens as a treatment. In view of the importance of immune complexes containing antibodies to nucleic acid antigens in SLE, the induction of tolerance to those antigens might provide a specific therapy for the disease. This idea is supported by evidence that tolerance to autoantigens can be induced by tolerogen (i.e., autoantigens covalently linked to isologous IgG). In addition, we have been able to link fragments of DNA long enough to accommodate the combining size of anti DNA antibodies made either by mice or humans with SLE to isologous IgG. Preliminary findings suggest that these tolerogens a) influence murine lupus, and b) diminish anti DNA antibodies in peripheral blood lymphocytes from SLE patients in vitro. This renewal seeks to confirm and extend these preliminary observations. We will determine if murine lupus in females of both BFW1 and MRL +/+ strain mice can be prevented or treated. We will also determine which DNA fragments conjugated to human gamma globulin are the best tolerogens to suppress either spontaneous or antigen induced antibodies to nucleic acid antigens in vitro. The goal is to develop the data bases for the induction of unresponsiveness to DNA in SLE patient. In addition, DNA digest linked to either KLH or tetanus toxoid will be used to develop an antigen specific model using normal lymphoid cells from various sources or SLE patient's PBL to study some aspects of the cellular mechanisms of both immunity and tolerance in humans in vitro.